Abstract Autoimmune posterior uveitis, a common cause of blindness, has an unknown etiology and no cure is available. Retinal antigen-specific T cell responses, especially Th17 cell responses, play an important role in the pathogenesis. Although CD6 was identified as a marker of T cells decades ago, its precise role in T cell regulation and the pathogenesis of diseases remains elusive, partly due to the lack of CD6 gene-engineered animals. In our pilot studies on experimental autoimmune uveitis (EAU) in CD6 knockout (KO) mice and using anti-CD6 monoclonal antibodies (mAbs) in wild type mice, we found evidence suggesting that CD6 is a critical T cell regulator in the pathogenesis of autoimmune uveitis and that targeting of CD6 using mAbs could be effective in treating this disease. In addition, we identified a novel CD6 ligand that could be more important for CD6 function than its currently known ligand (CD166) and showed that deficiency of this new CD6 ligand leads to attenuated EAU. In this project, using unique reagents developed by ourselves and provided by our collaborators, including CD6 KO mice, KO mice for either of the two CD6 ligands, CD6 humanized mice, EAU autoantigen- specific TCR transgenic mice, specific T cell-recognizing tetramers, and mouse anti-mouse CD6 function neutralizing mAbs that cross-react with human CD6, we will study mechanisms by which CD6 regulates the development of EAU by dissecting its role in regulating autoreactive T cell activation, proliferation, survival, and infiltration. We will also study the extent to which the CD6-targeted mAbs ameliorate EAU and the underlying mechanisms. These studies will clarify the controversy about the role of CD6 in regulating T cells generated by previous in vitro studies, help in understanding the mechanism by which CD6 regulates autoreactive T cell responses in the pathogenesis of autoimmune uveitis, and lay a solid foundation for the development of CD6-targeted mAbs as a new therapy for treating this blinding disease.